4-oxaprostaglandin e-type compounds

ABSTRACT

This invention is a group of 3-and 4-oxa PG-type compounds, and processes for making them. These compounds are useful for a variety of pharmacological purposes, including antiulcer, inhibition of platelet aggregation, increase of nasal patency, labor inducement at term, and wound healing.

United States Patent Nelson Nov. 18, 1975 4-OXAPROSTAGLANDIN E-TYPE 260/410; 260/424.4; 260/439 R; 260/448 R; COMPOUNDS 260/488 R; 260/50l.1; 260/501. I5; 260/501.17; 260/50l.2; 260/514 D [75] Inventor Galesburg 51 1111.0. c07c 61/38; c07c 69/71 [58] Field of Search 260/468 D, 514 D [73] Assignee: The Upjohn Company, Kalamazoo,

Mich. [56] References Cited [22] Filed: Apr. 17, 1974 FOREIGN PATENTS OR APPLICATIONS [2 pp Na: 4 1 543 2,036,471 Z/l97l Germany 260/468 Related Application Data Primary Examiner-Robert Gerstl [63] Continuation of Ser. No. 332,201, Feb. 13, 1973, Attorney, g or is ls n abandoned, which is a continuation-in-part of Ser. No. 272,444, July I7, 1972, abandoned, which is a [57] ABSTRACT 3232;232:25 of June This invention is a group of 3-and 4-0xa PG-type compounds, and processes for making them. These com- I Foreign Application Priority Data pounds are useful for a variety of pharmacological J l 19 purposes, including antiulcer, inhibition of platelet agu y 1969 Umted Kmgdom 38073/69 gregation, increase of nasal patency, labor inducement 52 US. Cl... 260/468 1); 260/211 R; 260/247.2 R; at term and Wound healmg' 70 Claims, No Drawings 4-OXA PROTAGLANDIN E-TYPE COMPOUNDS CROSS REFERENCE TO RELATED APPLICATIONS This application is a continuation of my copending application Ser. No. 332,201, filed Feb. 13, 1973, now abandoned, which was a continuation-in-part of my then copending application Ser. No. 272,444, filed July 17, 1972, now abandoned, which was a continuationin-part of my copending application Ser. No. 47,169, filed June 17, 1970, now abandoned.

BACKGROUND OF THE INVENTION This invention relates to compositions of matter, and to methods and intermediates for producing them. In particular, the several aspects of this invention relate to novel analogs of some of the known prostaglandins, for example, prostaglandin E 1 (PGE prostaglandin E (PGE prostaglandin F (PGF and PFG prostaglandin F (PGF and PGF prostaglandin A (PGA,), prostaglandin A (PGA prostaglandin B (PGB prostaglandin B (PGB the corresponding PG s, and the dihydro PG derivatives, to novel methods for producing those novel prostaglandin analogs, and to novel chemical intermediates useful in those novel methods.

Each of the above-mentioned known prostaglandins is a derivative of prostanoic acid which has the following structure and atom numbering:

A systematic name for prostanoic acid is 7-[(2,8-octyl)- cyclopentl a-yl]heptanoic acid.

PGE has the following structure:

PGA has the following structure:

HOH

PGB has the following structure:

OOH

Each of the known prostaglandins PGE PGF PGF PGA and PGB has a structure the same as that shown for the corresponding PG, compound ex cept that in each, C-5 and G6 are linked with a cis carbon-carbon double bond. For example, PGE has the following structure:

Vll

Each of the known PG prostaglandins has a structure the same as that of the PG compounds except that in each, C-17 and 018 are linked with a cis carboncarbon double bond. For example, PGE has the following structure:

Each dihydro derivative of PGE PGF PGF p PGA and PGB has a structure the same as that shown for the corresponding PG compound except that in each, C-l3 and C-l4 are linked with a carbon-carbon single bond. For example, dihydro-PGE has the following structure:

prostaglandin consists of equal numbers of two types of molecules, one represented by one of the above formulas and the other represented by the mirror image of that formula. Thus, both formulas are needed to define a racemic prostaglandin. See Nature 212, 38 (1966) for discussion of the stereochemistry of the prostaglandins.

In formulas I-lX, as well as in the formulas given hereinafter, broken line attachments to the cyclopentane ring indicate substituents in alpha configuration, i.e., below the plane of the cyclopentane ring. Heavy solid line attachments to the cyclopentane ring indicate substituents in beta configuration, i.e., above the plane of the cyclopentane ring.

Prostaglandins with carboxyl-terminated side chains attached to the cyclopentane ring in beta configuration are also known. These are derivatives of S-iso-prostanoic acid which has the following formula:

A systematic name for 8-iso-prostanoic acid is 7-[(2B- octyl)-cyclopent- 1 B-yllheptanoic acid.

The side-chain hydroxy at C in formulas 11 to IX is in alpha (S) configuration. See Nature 212, 38 (1966) for discussion of the stereochemistry of the prostaglandins.

PGE PGE dihydro-PGE and the corresponding PGF PGF PGA, and PGE compounds, and their esters, acylates, and pharmacologically acceptable salts, are extremely potent in causing various biological responses. For that reason, these compounds are useful for pharmocological purposes. See, for example, Bergstrom et al., Pharmacol. Rev. 20, l (1968), and references cited therein. A few of those biological responses are systemic blood pressure lowering in the case of the PGE and PGA compounds as measured,.for example, in anesthetized (pentobarbital sodium) pentoliniumtreated rats with indwelling aortic and right heart cannulas; stimulation of smooth muscle as shown, for example, by tests on strips of guinea pig ileum, rabbit duodenum, or gerbil colon; potentiation of other smooth muscle stimulants; antilipolytic activity as shown by antagonism of epinephrine-induced mobilization of free fatty acids or inhibition of the spontaneous release of glycerol from isolated rat fat pads; inhibition of gastric secretion in the case of the PGE and PGA compounds as shown in dogs with secretion stimulated by food or histamine infusion; activity on the central nervous system; controlling spasm and facilitating breathing in asthmatic conditions; decreasing blood platelet adhesiveness as shown by platelet-to-glass adhesiveness, and inhibition of blood platelet aggregation and thrombus formation induced by various physical stimuli, e.g., arterial injury, and various biochemical stimuli, e.g., ADP, ATP, serotonin, thrombin, and collagen; and in the case of the PGE and PGB compounds, stimulation of epidermal proliferation and keratinization as shown when applied in culture to embryonic chick and rat skin segments.

Because of these biological responses, these known prostaglandins are useful to study, prevent, control, or alleviate a wide variety of diseases and undesirable physiological conditions in birds and mammals, including humans, useful domestic animals, pets, and zoological specimens, and in laboratory animals, for example, mice, rats, rabbits, and monkeys.

For example, these compounds, and especially the PGE compounds, are useful in mammals, including man, as nasal decongestants. For this purpo e, the conpou'nds are used in a dose range of about 10 ,ug. to about 10 mg. per ml. of a pha rnacologically suitable liquid ehicle or as an aerosol spray, hoth for topical application.

Tue PGE, PGF PGF and PGA compounds are useful in the trea ment or asthma. For example, these compounds are useful as bronchodilators or as inhibitors of mediators, such as SRS-A, and histamine which are released from cells activated by an antigen-antibody complex. Thus, these compounds control spasm and facilitate breathing in conditions such as bronchial asthma, bronchitis, bron chiectasis, pneumonia and physema. For these purposes, these compounds are administered in a variety of dosage forms, e.g., orally in the of tablets, capsu es, liquids; rectelly in the form of suppositories; parenterally, subcuta usly, or intramuscularly, with intravenous administra-ion being preferred in emergency situations; by inhalation in the form of aerosols or solutions for ne ulizers; c: y 7fflation n the form of po der. Doses in the range of about 0.01 to 5 n g. per kg. of body eight are used 1 to 4 times a day, the exact dose depending on the age, weight, and condition of the patient and on the frequency and oute of administrat on. For the above use these prostaglandins can e combined advantageously with other anti-asthmatic agents, such as 53' ado nimetics (isoproterenol, phenylephrine, epher .e, e c); xanthine derivatives (theophylline and aminophylline); and corticosteroids (ACTH and predinisolone). Regarding use of these compounds see S uth African Pat. No. 681,055.

The PGE and PGA compounds are useful in mammals, including man and certain useful animals, e.g., dogs and pigs, to reduce and control excessi e gastric secret on, thereby reducing or avoiding gastrointestinal ulcer formation, and accelerating the healing of such ulcers already present in the gastrointestinal tract. For this purpose, the compounds are injected or i used intravenously, subcutaneously, or intramuscularly in an infusion dose range about 0.1 pg. to abo'fit 594) ug. per kg. of body weight per minute, or in a total daily dose by injection or infusion in the range about 6.1 to about 20 mg. per kg. of body weight per day, the exact dose depending on the age, weight, and condition of the atient or animal, and on the frequency and route of administration.

The PGE, PGF and PGFp compounds are useful whenever it is desired to inh bit platelet aggregation, to reduce the adhesive character of platelets, and to remove or prevent the formation of thrombi in mammals, including man, rabbits, and rats. For example, these compounds are useful in the treatment and prevention of myocardial infarcts, to treat and prevent post-operative thrombosis, to promote patency of vascular grafts following surgery, and to treat conditions such as atherosclerosis, arteriosclerosis, blood clotting defects due to lipemia, and other clinical conditions in which the underlying etiology is associated with lipid imbalance or hyperlipidemia. For these purposes, these compounds are administered systemically, e.g., intravenously, subcutaneously, intramuscularly, and in the form of sterile implants for prolonged action. For rapid response, especially in emergency situations, the intravenous route of administration is preferred. Doses in the range about 0.005 to about 20 mg. per kg. of body weight per day are used, the exact dose depending on the age, weight, and condition of the patient or animal, and on the frequency and route of administration.

The PGE, PGF and PGF compounds are especially useful as additives to blood, blood products, blood substitutes, and other fluids which are used in artificial extracorporeal circulation and perfusion of isolated body portions, e.g., limbs and organs, whether attached to the original body, detached and being preserved or prepared for transplant, or attached to a new body. During these circulations and perfusions, aggregated platelets tend to block the blood vessels and portions of the circulation apparatus. This blocking is avoided by the presence of these compounds. For this purpose, the compound is added gradually or in single or multiple portions to the circulating blood, to the blood of the donor animal, to the perfused body portion, attached or detached, to the recipient, or to two or all of those at a total steady state dose of about 0.001 to mg. per liter of circulating fluid. It is especially useful to use these compounds in laboratory animals, e.g., cats, dogs, rabbits, monkeys, and rats, for these purposes in order to develop new methods and techniques for organ and limb transplants.

PGE compounds are extremely potent in causing stimulation of smooth muscle, and are also highly active in potentiating other known smooth muscle stimulators, for example, oxytocic agents, e.g., oxytocin, and the various ergot alkaloids including derivatives and analogs thereof. Therefore, PGE for example, is useful in place of or in combination with less than usual amounts of these known smooth muscle stimulators, for example, to relieve the symptoms of paralytic ileus, or to control or prevent atonic uterine bleeding after abortion or delivery, to aid in expulsion of the placenta, and during the puerperium. For the latter purpose, the PGE compound is administered by intravenous infusion immediately after abortion or delivery at a dose in the range about 0.01 to about 50 pg. per kg. of body weight per minute until the desired effect is obtained. Subsequent doses are given by intravenous, subcutaneous, or intramuscular injection or infusion during puerperium in the range 0.01 to 2 mg. per kg. of body weight per day, the exact dose depending on the age, weight, and condition of the patient or animal.

The PGE and PGA compounds are useful as hypotensive agents to reduce blood pressure in mammals, including man. For this purpose, the compounds are administered by intravenous infusion at the rate about 0.01 to about 50 pg. per kg. of body weight per minute or in single or multiple doses of about 25 to 500 1.1g. per kg. of body weight total per day.

The PGE, PGF and PGF compounds are useful in place of oxytocin to induce labor in pregnant female animals, including man, cows, sheep, and pigs, at or near term, or in pregnant animals with intrauterine death of the fetus from about weeks to term. For this purpose, the compound is infused intravenously at a dose of 0.01 to 50 pg. per kg. of body weight per minute until or near the termination of the second stage of labor, i.e., expulsion of the fetus. These compounds are especially useful when the female is one or more weeks post-mature and natural labor has not started, or 12 to 60 hours after the membranes have ruptured and natural labor has not yet started. An alternative route of administration is oral.

The PGE, PGF and PGF compounds are useful for controlling the reproductive cycle in ovulating female mammals, including humans and animals such as monkeys, rats, rabbits, dogs, cattle, and the like. By the term ovulating female mammals is meant animals which are mature enough to ovulate but not so old that regular ovulation has ceased. For that purpose PGF for example, is administered systemically at a dose level in the range 0.01 mg. to about 20 mg. per kg. of body weight of the female mammal, advantageously during a span of time starting approximately at the time of ovulation and ending approximately at the time of menses or just prior to menses. lntravaginal and intrauterine are alternative routes of administration. Additionally, expulsion of an embryo or a fetus is accomplished by similar administration of the compound during the first third of the normal mammalian gestation period.

The PGE and PGF compounds are useful in causing cervical dilation in pregnant and nonpregnant female mammals for purposes of gynecology and obstetrics. In labor induction and in clinical abortion produced by these compounds, cervical dilation is also observed. In cases of infertility, cervical dilation produced by PGE and PGF compounds is useful in assisting sperm movement to the uterus. Cervical dilation by prostaglandins is also useful in operative gynecology such as D and C (Cervical Dilation and Uterine Curettage) where mechanical dilation may cause perforation of the uterus, cervical tears, or infections. It is also useful in diagnostic procedures where dilation is necessary for tissue examination. For these purposes, the PGE and PGF compounds are administered locally or systemically. PGE for example, is administered orally or vaginally at doses of about 5 to 50 mg. per treatment of an adult female human, with from one to five treatments per 24 hour period. PGE is also administered intramuscularly or subcutaneously at doses of about one ot 25 mg. per treatment. The exact dosages for these purposes depend on the age, weight, and condition of the patient or animal.

As mentioned above, the PGE compounds are potent antagonists of epinephrine-induced mobilization of free fatty acids. For this reason, this compound is useful in experimental medicine for both in vitro and in vivo studies in mammals, including man, rabbits, and rats, intended to lead to the understanding, prevention, symptom alleviation, and cure of diseases involving abnormal lipid mobilization and high free fatty acid levels, e. g., diabetes mellitus, vascular diseases, and hyperthyroidisr'n.

The PGA compounds and derivatives and salts thereof increase the flow of blood in the mammalian kidney, thereby increasing volume and electrolyte content of the urine. For that'reason, PGA compounds are useful in managing cases of renal disfunction, especially those involving blockage of the renal vascular bed. Illustratively, the PGA compounds are useful to alleviate and correct cases of edema resulting, for example, from massive surface burns, and in the management of shock. For these purposes, the PGA compounds are preferably first administered by intravenous injection at a dose in the range of 10 to 1000 pg per kg. of body weight or by intravenous infusion at a dose in the range 0.1 to 20 pg. per kg. of body weight per minute until the desired effect is obtained. Subsequent doses are given by intravenous, intramuscular, or subcutaneous injection or infusion in the range 0.05 to 2 mg. per kg. of body weight per day.

The PGE and PGB compounds promote and accelerate the growth of epidermal cells and keratin in animals, including humans, useful domestic animals, pets, zoological specimens, and laboratory animals. For that reason, these compounds are useful to promote and accelerate healing of skin which has been damaged, for example, by burns, wounds, and abrasions, and after surgery. These compounds are also useful to promote and accelerate adherence and growth of skin autografts, expecially small, deep (Davis) grafts which are intended to cover skinless areas by subsequent outward growth rather than initially, and to retard rejection of homografts.

For these purposes, these compounds are preferably administered topically at or near the cite where cell growth and keratin formation is desired, advantageously as an aerosol liquid or micronized powder spray, as an isotonic aqueous solution in the case of wet dressings, or as a lotion, cream, or ointment in combination with the usual pharmaceutically acceptable diluents. In some instances, for example, when there is substantial fluid loss as in the case of extensive burns or skin loss due to other causes, systemic administration is advantageous, for example, by intravenous injection or infusion, separate or in combination with the usual infusions of blood, plasma, or substitutes thereof. Alternative routes of administration are subcutaneous or intramuscular near the site, oral, subligual, buccal, rectal, or vaginal. The exact dose depends on such factors as the route of administration, and the age, weight, and condition of the subject. To illustrate, a wet dressing for topical application to second and/or third degree burns of skin rea 5 to 25 square centimeters would advantageously involve use of an isotonic aqueous solution containing 1 to 500 ug/ml. of the PGB compound or several times that concentration of the PGE compound. Especially for topical use, these prostaglandins are useful in combination with antibiotics, for example, gentamycin, neomycin, polymyxin B, bacitracin, spectinomycin, and oxytetracycline, with other antibacterials, for example, mafenide hydrochloride, sulfadiazine, furazolium chloride, and nitrofurazone, and with corticoid steroids, for example, hydrocortisone, prednisolone, methylprednisolone, and fluprednisolone, each of those being used in the combination at the usual concentration suitable for its use alone.

SUMMARY OF THE INVENTION 0 coon The novel compound, 4-oxa-PGE is represented by the formula:

Some of the novel prostaglandin analogs of this invention have a smaller or greater number of carbon atoms than the formulas shown above, in either the carboxy-terminated side chain or the alkyl-terminated side chain.

For example, five of the novel prostaglandin analogs of this invention are represented by the formulas:

Xlll

XIV

CH C C-CH=-O-CH COOH XVI H OH X Vll Based on its relationship to PGE, and prostanoic acid, the compound of formula XIII is named 3-oxa-4-nor- PGE the compound of formula XIV is named 4-oxa- 4a,4b-dihomo-l3,14-dihydro-1S-beta-PGF, a the compound of formula XV is named 3-oxa-l9,20-dinor- PGA ;the compound of formula XVI is named 3-oxa- 9 5,6-dehydro-2O-methyl-PGB and the compound of formula XVII is named 3-oxa-4a-homo-PGF These names for the compounds of formulas XIII to XVII are typical of the names used hereinafter for the novel compounds of this invention. These names can better be understood by reference to the structure and numbering system of prostanoic acid (Formula I, above). That formula has seven carbon atoms in the carboxy-terminated chain and eight carbon atoms in the hydroxy-containing chain. In these names, 3oxa and 4-oxa indicate an oxa oxygen (O) in place of the 3-methy1ene and 4-methylene, respectively of the PG compound.

The use of nor or dinor in the names for the novel compounds of this invention indicates the absence of one or two of the chain carbon atoms and the attached hydrogen atoms. The number or numbers in front of nor, or dinor indicate which of the original prostanoic acid carbon atoms are missing in the named compound.

The use of homo or dihomo as in the names of the formula-XIV and -XVII examples indicate one or two additional carbon atoms in the carboxy-terminated side chain. In the name of the formula-XIV example 4a,4b-dihomo indicates two additional carbon atoms specifically between the oxygen atom at 4 and the C-5 carbon atom. There are, therefore, eight carbon atoms and one oxygen atom in that side chain instead of the six carbon atoms and one oxygen atom of the normal 3-oxa structure of this invention.

In the name of the formula-XVI example, 20- methyl indicates that a methyl group replaces a hydrogen on C-20. The methyl-terminated chain of that example therefore has nine carbon atoms.

Where there is branching or fluoro substitution in the side chains, the points of attachment to the side chains are indicated in the conventional manner, following the atomic numbering of the prostanoic acid skeleton (I).

Novel compounds of this invention with epi configuration for the hydroxy at C-l5 are so designated by using IS-beta in the name. An example is the name given above for the compound of formula XIV. If beta does not appear in the name, the natural configuration for the C-15 hydroxy, identified as the S configuration for PGE is to be assumed.

The following formulas represent the novel 3-oxa and 4-oxa compounds of this invention in the same optically active form as the naturally occurring prostaglandins.

-c ontinued XXXVI XXXVHI Formulas XVIII to XXVII represent 3-oxa and 4-oxa compounds of the PGE type. Formulas XXVIII to XXXVII represent 3-oxa and 4-oxa compounds of the PGF type. Formulas XXXVIII to XLVII represent 3-oxa and 4-oxa compounds of the PGA type. Formulas XLVIII to LVII represent 3-oxa and 4-oxa compounds of the PGB type.

In formulas XVIII to LVII, R is hydrogen, alkyl of one to 12 carbon atoms, inclusive, cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, phenyl substituted with one to 3 chloro or alkyl of one to 4 carbon atoms, inclusive, or ethyl substituted in the B-position with 3 chloro, 2 or 3 bromo, or 1, 2, or 3 iodo. R is alkyl of one to 10 carbon atoms, inclusive, substituted with zero to 3 fluoro. Q is R, OH

R OH wherein R is hydrogen or alkyl of one to 4 carbon atoms, inclusive. R is alkyl of one to 4 carbon atoms, inclusive, substituted with zero, one, 2, or 3 fluoro. R R R and R are hydrogen or alkyl of one to 4 carbon atoms, inclusive. The divalent moiety C I-I represents alkylene of one to 10 carbon atoms, inclusive, with one to 5 carbon atoms, inclusive, between -CH and O. The divalent moiety C,,,I-I represents alkylene of one to 9 carbon atoms, inclusive, with one to 4 carbon atoms, inclusive, between CH and O. The divalent moiety C H represents alkylene of one to 8 carbon atoms, inclusive, with one, 2, or 3 carbon atoms between CH=CH- or C s C and O. The divalent moiety C I-I- represents alkylene of one to 7 carbon atoms, inclusive, with one of 2 carbon atoms between CI-I=. CH or C n C and O. The divalent moiety C H represents alkylene of one to 4 carbon atoms, inclusive. The wavy line indicates attachment of the hydroxyl group to the ring in alpha or beta configuration.

Formulas XVIII through LVII include the separate isomers wherein Q is either R, on

R OH,

i.e., where the hydroxyl is in either alpha (natural) or beta configuration. Referring to the prostanoic acid atom numbering (formula I above), the point of attachment corresponds to C-l5, and, herein, regardless of the variation in the C-1 to C-7 carboxy chain, these epimers are referred to as C-l5 epimers.

Formulas XXVIII through XXXVII wherein the C-9 hydroxyl (following prostanoic acid atom numbering) 16 is attached to the cyclopentane with a wavy line include both PGF and PGF type compounds.

Included in formulas XX, XXI, XXX, XXXI, XL, XLI, L, and LI are both the cis and the trans compounds with respect to the C-5 to C-6 double bond in the carboxyl-terminated side chain. In all of the compounds containing the C -to-C double bond, that double bond is in trans configuration, and the chain containing that moiety is attached to the cyclopentane ring in beta configuration in compounds encompassed by formulas XVIII to XLVll.

The novel 3-oxa and 4-oxa compounds of this invention include racemic compounds and both optically active enantiomeric forms thereof. As discussed hereinabove, two structural formulas are required to define accurately these racemic compounds. The formulas as drawn herein are intended to represent compounds with the same configuration as the naturally-occurring prostaglandins. However, for convenience in the charts herein only a single structural formula is used, for example in Chart E, to define not only the optically active form but also the racemic compounds which generally undergo the same reactions.

Formula XVIII represents 3-oxa-PGE (formula XI hereinabove) when C,,I-I is -(CI-I Q is H OH.

R R and R are hydrogen, and R is n-pentyl.

With regard to formulas XVIII to LVII, examples of alkyl of one to 4 carbon atoms, inclusive, are methyl, ethyl, propyl, butyl, and isomeric forms thereof. Examples of alkyl of one to 8 carbon atoms, inclusive, are those given above, and pentyl, hexyl, heptyl, octyl, and isomeric forms thereof. Examples of alkyl of one to 12 carbon atoms, inclusive, are those given above, and nonyl, decyl, undecyl, dodecyl, and isomeric forms thereof. Examples of cycloalkyl of 3 to 10 carbon atoms, inclusive, which includes alkyl-substituted cycloalkyl, are cyclopropyl, Z-methylcyclopropyl, 2,2- dimethylcyclopropyl, 2,3-diethylcyclopropyl, Z-butylcyclopropyl, cyclobutyl, 2-methylcyclobutyl, 3-propylcyclobutyl, 2,3,4-triethylcyclobutyl, cyclopentyl, 2,2- dimethylcyclopentyl, 3-pentylcyclopentyl, 3-tert-butylcyclopentyl, cyclohexyl, 4-tert-butylcyclohexyl, 3-isopropylcyclohexyl, 2,2-dimethylcyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl. Examples of aralkyl of 7 to 12 carbon atoms, inclusive, are benzyl, phenethyl, l-phenylethyl, 2-phenylpropyl, 4- phenylbutyl, 3-phenylbutyl, 2-( l-naphthylethyl), and l-(2-naphthylmethyl). Examples of phenyl substituted by one to 3 chloro or alkyl of one to 4 carbon atoms, inclusive, are p-chlorophenyl, m-chlorophenyl, ochlorophenyl, 2,4-dichlorophenyl, 2,4,6-trichlorophenyl, p-tolyl, m-tolyl, o-tolyl, p-ethylphenyl, p-tert-butyb phenyl, 2,5-dimethylphenyl, 4-chloro-2-methylphenyl, and 2,4,-dichloro-3-methylphenyl.

Examples of alkyl of one to 10 carbon atoms, inclusive, substituted with one to 3 fluoro, are fluoromethyl, 2-fluoroethyl, 2-fluorobutyl, 3-fluorobutyl, 4-fluorobutyl, S-fluoropentyl, 4-fluoro-4-methylpentyl, 3- fluoroisoheptyl, 8-fluorooctyl, 3,4-difluorobutyl, 4,4- difluoropentyl, 5,5-difluoropentyl, 5,5,5-trifluoropentyl, and 10,10,10-trifluorodecyl.

Examples of alkylene within the various scopes of C ,-l-I C I-I C,,H C l-I and C l-I as those are de- 17 fined above, are methylene, ethylene, trimethylene, tetramethylene, pentarnethylene, and those alkylene with one or more alkyl substituents on one or more carbon The novel formula XVIII-XXVII PGE-type 3-oxa and 4-oxa compounds, the novel formula XXVIII-XXXVII PGF -type and PGF -type 3-oxa and 4-oxa compounds, the novel formula XXXVIII-XLVII PGA-type 3-oxa and 4-oxa compounds, and the novel formula XLVIII-LVII PGB-type 3-oxa and 4-oxa compounds, and their racemic forms, each cause the biological responses described above for the P65, PGF PGF PGA, and PGE compounds, respectively, and eac of these novel compounds is accordingly usefulfor the above-described corresponding purposes, and is used for those purposes in the same manner as described above.

The known PGE, PGFa PGF PGA, and PGB compounds uniformly cause mufiiple biological responses even at low doses. For example, PGE and PGE both cause vasodepression and smooth muscle stimulation at the same time they exert antilipolytic activity. Moreover, for many applications, these known prostaglandins have an inconveniently short duration of biological activity. In striking contrast, the novel formula XVIII-toLVII analogs and their racemic forms are substantially more specific with regard to potency in causing prostaglandin-like biological responses, and have a substantially longer duration of biological activity. Therefore, each of these novel prostaglandin analogs is useful in place of one of the corresponding above-mentioned known prostaglandins for at least one of the pharmacological purposes indicated above for the latter, and is surprisingly and unexpectedly more useful for that purpose because it has a different and narrower spectrum of biological activity than the known prostaglandin, and therefore is more specific in its activity and causes smaller and fewer undesired side effects than the known prostaglandin. Moreover, because of its prolonged activity, fewer and smaller doses of the novel prostaglandin analog can frequently be used to attain the desired result.

To obtain the optimum combination of biological potency specificity and duration of activity, certain com pounds within the scope of formulas XVIII to LVII are preferred. For example, it is preferred that the carboxyterminated chain in each formula contain a chain of six atoms between the carboxyl and the cyclopentane ring. One of those six atoms will be the oxa atom and the other five will be carbon atoms. Accordingly and with reference to formulas XVIII to LVII, it is preferred that -C,,H represent a 3-carbon divalent chain, that -C,,,H represent a 2-carbon divalent chain, and that C,,II represent a divalent carbon atom. These preferences do not exclude additional carbon atoms (alkyl groups) as branching.

A seven-atom carboxyl terminated chain is not included in the compounds of formulas XXI, XXIII, XXVII, XXXI, XXXIII, XXXVII, XLI, XLIII, XLVII, LI, LIII, and LVII, i.e., formulas wherein the carboxyterminated side chain is 4-oxa and contains a carboncarbon double or triple bond. In each of those compounds, the q of -C,,H is at least one, and at least seven atoms, one oxygen (oxa) and six carbons, are present between the carboxyl and the cyclopentane ring. In these compounds, the preference is for that minimum chain, i.e., q is one.

Another preference for the compounds of formulas XVIII to LVII is that R R R R and R, be hydrogen or methyl. All of those R groups can be hydrogen, all can be methyl, or there can be any of the possible combinations of hydrogen and methyl, It is especially preferred for prolonged duration of biological activity that both R and R be methyl, and/or that R be methyl.

Certain variations in the nature of R in formulas XVIIIXXV, XXVIII-XXXV, XXXVIII-XLV, and XLVIII-LV are especially important. In the known prostaglandins, e.g., PGE the portion of the molecule corresponding to R in the above-mentioned formulas is pentyl. It is preferred that R be pentyl in formulas XVIII-XXV, XXVIII-XXXV, XXXVII-XLV, and XLVIII-LV. It is also preferred that R be straight chain alkyl of 3 to 7 carbon atoms, inclusive, with or without a fluoro substituent at the l-position, e.g., CI-IF(CI-I CI-I wherein g is one to 5. Alter nately, R is represented by wherein R is, hydrogen or fluoro and g is one, 2, 3, 4, or 5. Pentyl and l-fiuoropentyl are, of course, included in this preference.

In compounds of formulas XXVI, XXVII, XXXVI, XXXVII, XLVI, XLVII, LVI, and LVII, it is preferred that C I-I be methylene and that R be ethyl.

Another advantage of the novel compounds of this invention, especially the preferred compounds defined hereinabove, compared with the known prostaglandins, is that these novel compounds are administered effectively orally, sublingually, intravaginally, buccally, or rectally, in addition to usual intravenous, intramuscular, or subcutaneous injection or infusion methods indicated above for the uses of the known prostaglandins. These qualities are advantageous because they facilitate maintaining uniform levels of these compounds in the body with fewer, shorter, or smaller doses, and make possible self-administration by the patient.

The PGE, PGF PGF PGA, and P68 type 3-oxa and 4-oxa compounds encompassed by formulas XVIII to LVII including the special classes of compounds described above, are used for the purposes described above in the free acid form, in ester form, or in pharmacologically acceptable salt form. When the ester form is used the ester is any of those within the above definition of R However, it is preferred that the ester be alkyl of one to 12 carbon atoms, inclusive. Of those alkyl, methyl and ethyl are especially preferred for optimum absorption of the compound by the body or experimental animal system; and straight-chain octyl, nonyl,, decyl, undecyl, and dodecyl are especially preferred for prolonged activity in the body or experimental animal.

Pharmacologically acceptable salts of these formula XVIII-to-LVII compounds useful for the purposes described above are those with pharmacologically acceptable metal cations, ammonium, amine cations, or quaternary ammonium cations.

Especially preferred metal cations are those derived from the alkali metals, e.g., lithium, sodium and potassium, and from the alkaline earth metals, e.g., magnesium and calcium, although cationic forms of other metals, e.g., aluminum, zinc, and iron, are within the scope of this invention.

Phannacologically acceptable amine cations are those derived from primary, secondary, or tertiary amines. Examples of suitable amines are methylamine, dimethylamine, trimethylamine, ethylamine, dibutylamine, triisopropylamine, N-methylhexylamine, decylamine, dodecylamine, allylamine, crotylamine, cyclopentylamine, dicyclohexylamine, benzylamine, dibenzylamine, a-phenylethylamine, ,B-phenylethylamine, etheylenediamine, diethylenetriamine, and like aliphatic, cycloaliphatic, and araliphatic amines containing up to and including about 18 carbon atoms, as well as heterocyclic amines, e.g., piperidine, morpholine, pyrrolidine, piperazine, and lower-alkyl derivatives thereof, e.g., l-methylpiperidine, 4-ethylmorpholine, l-isopropylpyrrolidine, 2-methylpyrrolidine, 1,4- dimethylpiperazine, 2-methylpiperidine, and the like, as well as amines containing water-solubilizing or hydrophilic groups, e.g., mono-, di-, and triethanolamine, ethyldiethanolamine, N-butylethanolamine, 2-aminol-butanol, 2-amino-2-ethyl-1,3-propanediol, Z-amino- 2-methyl- 1 -propanol, tris-(hydroxymethyl)arninomethane, N-phenylethanolamine, N-(p-tert-amylphenyl)- diethanolamine, galactamine, N-methylglucamine, N- methylglucosamine, ephedrine, phenylephrine, epinephrine, procaine, and the like.

Examples of suitable pharmacologically acceptable quaternary ammonium cations are tetramethylammonium, tetraethylammonium, benzyltrimethylammonium, phenyltriethylammonium, and the like.

The 3-oxa and 4-oxa PGE, PGF PGF PGA, and PGE type compounds encompassed by formulas XVlll to LVll including the special classes of compounds described above, are also used for the purposes described above in free hydroxy form or in the form wherein the hydroxy moieties are transformed to lower alkanoate moieties, e.g., OH to OCOCH Examples of lower alkanoate moieties are acetoxy, propionyloxy, butyryloxy, valeryloxy, hexanoyloxy, heptanoyloxy, octanoyloxy, and branched chain alkanoyloxy isomers of those moieties. Especially preferred among these alkanoates for the above described purposes are the acetoxy compounds. These free hydroxy and alkanoyloxy compounds are used as free acids, as esters, and in salt form all as described above.

As discussed above, the compounds of formulas XVlll to LVII are administered in various ways for various purposes; e.g., intravenously, intramuscularly, subcutaneously, orally, intravaginally, rectally, buccally, sublingually, topically, and in the form of sterile implants for prolonged action. For intravenous injection or infusion, sterile aqueous isotonic solutions are preferred. For that purpose, it is preferred because of increased water solubility that R in the formula XVIII- to-LVII compound be hydrogen or a pharmacologically acceptable cation. For subcutaneous or intramuscular injection, sterile solutions or suspensions of the acid, salt, or ester form in aqueous or non-aqueous media are used. Tablets, capsules, and liquid preparations such as syrups, elixirs, and simple solutions, with the usual pharmaceutical carriers are used for oral sublingual administration. For rectal or vaginal administration, suppositories prepared as known in the art are used. For

20 tissue implants, a sterile tablet or silicone rubber capsule or other object containing or impregnated with the substance is used.

The 3-oxa and 4-oxa PGE, PGF PGF PGA, and PGB type compounds encompassed by formulas XVIII to LVII are produced by the reactions and procedures described and exemplified hereinafter.

The various 3-oxa and 4-oxa PGF -type and PGF -type compounds encompassed by formulas XXVlll-XXXVII are prepared by carbonyl reduction of the corresponding PGE type compounds encompassed by formulas XVllI-XXVII. For example, carbonyl reduction of 3-oxa PGE gives a mixture of 3-oxa PGF and 3-oxa PGF These ring carbonyl reductions are carried out by methods known in the art for ring carbonyl reductions of known prostanoic acid derivatives. See, for example, Bergstrom et al., Arkiv Kemi 19, 563 (1963), Acta Chem. Scand. 16, 969 (1962), and British Specification No. 1,097,533. Any reducing agent is used which does not react with carbon-carbon double bonds or ester groups. Preferred reagents are lithium(tri-tertbutoxy)aluminum hydride, the metal borohydrides, especially sodium, potassium and zinc borohydrides, and metal trialkoxy borohydrides, e.g., sodium trimethoxyborohydride. The mixtures of alpha and beta hydroxy reduction products are separated into the individual alpha and beta isomers by methods known in the art for the separation of analogous pairs of known isomeric prostanoic acid derivatives. See, for example, Bergstrom et al., cited above, Granstrom et al., J. Biol. Chem. 240, 457 (1965), and Green et al., J. Lipid Research 5, 117 (1964). Expecially preferred as separation methods are partition chromatographic procedures, both normal and reversed phase, preparative thin layer chromatography, countercurrent distribution procedures, and column chromatography.

The various 3-oxa and 4-oxa PGA-type compounds encompassed by formulas XXXVlIl-XLVII are prepared by acidic dehydration of the corresponding PGE type compounds encompassed by formulas XVIII- XXVII. For example, acidic dehydration of 3-oxa PGE, gives 3-oxa PGA,. 7

These acidic dehydrations are carried out by methods known in the art for acidic dehydrations of known prostanoic acid derivatives. See, for example, Pike et al., Proc. Nobel Symposium ll, Stockholm (1966), interscience Publishers, New York, pp. 162-163 (1967); and British Specification No. 1,097,533. Alkanoic acids of 2 to 6 carbon atoms, inclusive, especially acetic acid, are preferred acids for this acidic dehydration. Dilute aqueous solutions of mineral acids, e.g., hydrochloric acid, especially in the presence of a solubilizing diluent, e.g., tetrahydrofuran, are also useful as reagents for this acidic dehydration, although these reagents may cause partial hydrolysis of an ester reactant.

The various 3-oxa and 4-oxa PGB-type compounds encompassed by formulas XLVll-LVII are prepared by basic dehydration of the corresponding PGE type compounds encompassed by formulas XVIII-XXV ll, or by contacting the corresponding PGA compounds encompassed by formulas XXXVlll-XLVII with base. For example, both 3-oxa PGE, and 3-oxa PGA give 3-oxa PGB on treatment with base.

These basic dehydrations and double bond migrations are carried out by methods known in the art for similar reactions of known prostanoic acid derivatives. See, for example, Bergstrom et al., J. Biol. Chem.

238,3555 (1963). The base is any whose aqueous solution has pI-I greater than 10. Preferred bases are the alkali metal hydroxides. A mixture of water and suffrcient of a water-miscible alkanol to give a homogeneous reaction mixture is suitable as a reaction medium. The PGE-type or PGA-type compound is maintained in such a reaction medium until no further PGB-type compound is formed, as shown by the characteristic ultraviolet light absorption near 278 nm for the PGB type compound.

The various transformations of 3-oxa and 4-oxa PGE type compounds of formulas XVIII to XXV to the corresponding 3-oxa and 4-oxa PGF PGF PGA, and PGB type compounds are shown in Chart A, wherein Q, R,, R and are as defined above, and wherein A is CI-I -CH or transCH=CH-, Q is CMRT A it ,cn -v-cooa, A-C-R H6 in Q aci d ,CH V-COOR; base 'C'Rg ll carbonyl Q reduction i base ,ICHQ'VCOOR,

A -fi Rz H6 Q 22 R. on

R OH.

and V is C,,I-I ,,-OCR R C,,,H ,,,O-CR R6 CR7R8 or trans), CI-I=CI-l-C I-l OCR R -CR R (cis or trans), C I C--C,,H OCR R or C- I C-C l-I --O-CR R CR R wherein R R R7 s n 2m ur 21m CDHZP and q 2a are as defined above, with the proviso that V is -C,,II ,,O-CR R or C,,,H ,,,OCR R CR-,R when A is --CH -Cl-I The 3-oxa and 4-oxa PGE type compounds of formulas XXVI and XXVII are transformed to the corresponding 3-oxa and 4-oxa PGF PGF PGA and PGB compounds by analogous reactions.

The various 3-oxa and 4-oxa dihydro-PGE dihydro- PGF dihydro-PGF p dihydro-PGA and dihydro-PGB type compounds encompassed by formulas XXIV, XXV, XXXIV, XXXV, XLIV, XLV, LIV, and LV are prepared by carbon-carbon double bond reduction of the corresponding PGE, PGF PGF PGA, and PGB type compound containing a trans double bond in the hydroxy-containing side chain. A cis or trans double bond or an acetylenic bond can also be present in the carboxy-terminated side chain of the unsaturated reactant, and will be reduced at the same time to CH CH For example, dihydro-3-oxa- PGE is produced by reduction of 3-oxa-PGE 3-oxa- PGE or 5,6-dehydro-3-oxa-PGE These reductions are carried out by reacting the unsaturated PGE, PGF PGF PGA, or PGB type compound with diimide, following the general procedure described by van Tamelen et al., J. Am. Chem. Soc., 83, 3726 (1961). See also Fieser et al., Topics in Organic Chemistry, Reinhold Publishing Corp., New York, pp. 432-434 1963) and references cited herein. The unsaturated acid or ester reactant is mixed with a salt of azodiformic acid, preferably an alkali metal salt such as the disodium or dipotassium salt, in the presence of an inert diluent, preferably a lower alkanol such as methanol or ethanol, and preferably in the absence of substantial amounts of water. At least one molecular equivalent of the azodiformic acid salt is used for each multiple bond equivalent of the unsaturated reactant. The resulting suspension is then stirred, preferably with exclusion of oxygen, and the mixture is made acid, advantageously with a carboxylic acid such as acetic acid. When a reactant wherein R, is hydrogen is used, that carboxylic acid reactant also serves to acidify an equivalent amount of the azodiformic acid salt. A reaction temperature in the range about 10 to about 40 C. is usually suitable. Within that temperature range, the reaction is usually complete within less than 24 hours. The desired dihydro product is then isolated by conventional methods, for example, evaporation of the diluent, followed by separation from inorganic materials by solvent extraction.

In the case of the 3-oxa and 4 oxa unsaturated PGE, PGF and P6P; type reactants, the reductions to the corresponding 3-oxa and 4-oxa dihydro-PGE,,

23 dihydro-PFG and CllhYdI'O-PGF B compounds are also carried out by catalytic hydrogenation. For that purpose, palladium catalysts, expecially on a carbon carrier, are preferred. It is also preferred that the hydrogenation be carried out in the presence of an inert liquid diluent, for example, methanol, ethanol, dioxane, ethyl acetate, and the like. Hydrogenation pressures ranging from about atmospheric to about 50 p.s.i., and hydrogenation temperatures ranging from about to about 100 C. are preferred. The resulting dihydro product is isolated from the hydrogenation reaction mixture by conventional methods, for example, removal of the catalyst by filtration or centrifugation, followed by evaporation of the solvent.

Diimide reductions and catalytic hydrogenations to produce the various novel 3-oxa and 4-oxa dihydro compounds of this invention from the corresponding 3-oxa and 4-oxa PGE PGF PGF PGA and PGB type compounds are shown in Chart B, wherein Q, R, R and are as defined above, and W is -C,,H- 2n 5 fi or m 2m 5 6 7 8 a wherein C,,H C,,,H R R R and R are as defined above.

CHART B H C=C Hd H E- R diimide or hydrogen catalyst CH W COOR 5;

I CH CH -C-R, I HO g /CH. .W-COOR,

' c=c A H H CR,

diimide or hydrogen catalyst CH W-COOR, @CFMCH E- z H 6 diimide These diimide reductions and catalytic hydrogena- -tions to produce the same novel 3-oxa and 4-oxa dihydro compounds of this invention from the corresponding 3-oxa and 4-oxa PGE PGF PGF p', PGA and PGB type compounds and also from the corresponding compounds with a trans-ethylenic or an acetylenic linkage in place of the cis-ethylenic linkage in the carboxyl-terminated side chain, are shown in Chart C, wherein Q, R R and are as defined above, U is cisCH=CH-, transCH=CH-, or C C, and Y is C H OCR R 0t 'C H2 'OCR5. R CR R wherein p, q, R R R and R are as defined above.

The 3-oxa and 4-oxa compounds of the PGE PGF PGF PGA and P68 type wherein the carbon-carbon double bond in the carboxy-terminated side chain is in cis configuration are prepared by reduction of the corresponding acetylenic 3-oxa and 4-oxa compounds, i.e., those with a carbon-carbon triple bond in place of said carbon-carbon double bond. For that purpose, there are used any of the known reducing agents which reduce an acetylenic linkage to a cis-ethylenic linkage. Especially preferred for that purpose are diimide or hydrogen and a catalyst, for example, palladium (5%) on barium sulfate, especially in the presence of pyridine. See Fieser et al., Reagents for Organic Synthesis, pp. 566-567, John Wiley & Sons, Inc., New York, NY. (1967). These reductions are shown in Chart D, wherein Q, R R and are as de- -continued CHART C diimide or hydrogen catalyst CH CH CH -YCOOR,

CHART D -continued cH, c C Y cooR,

The 3-oxa and 4-oxa PGE type compounds of formulas XVIII to XXIII except wherein R is hydrogen, and the 3-oxa and 4-oxa PGA type compounds of formulas XXXVIII to XLIII except wherein R is hydrogen are prepared by the series of reactions shown in Chart E, wherein Q, R and V are as defined above, R and R are alkyl of one to 4 carbon atoms, inclusive R is the same as the above definition of R except that R does not include hydrogen, R is alkyl of one to 5 carbon atoms, inclusive, and indicates exo or endo configuration with respect to the moiety attached to the cyclopropane ring.

The 3-oxa and 4-oxa PGE type compounds of formulas XVIII and XIX, the 3-oxa and 4-oxa 5,6-dehydro-PGE type compounds of formulas XXII and XXIII, the 3-oxa and 4-oxa PGA type compounds of formulas XXXVIII and XXXIX, and the 3-oxa and 4-oxa 5,6-dehydro-PGA type compounds of formulas XLII and XLIII are also prepared by the series of reactions shown in Chart F, wherein Q, R R R and R are as defined above, Z is C,,H ,,OCR R C, H ,,,OCR R CR R,,, C E CC,,H-

28 ,,OCR R or C E CC H O-CR R ,-CR R,,, and indicates exo or endo configuration with respect to the moiety attached to the cyclopropane ring.

It should be observed regarding the series of reactions shown in Charts E and F, that the reaction starting with glycol LX in Chart E are similar to the reactions starting with glycol LXVII in Chart F. The only d fferences here are the definitions of the divalent moieties (Chart E) and Z (Chart F). V includes saturated, C15 and trans ethylenic, and acetylenic divalent moieties. is limited to the saturated and acetylenic divalent moieties encompassed by V.

CHART E LVIII LIX I OH

LXI

l oso R,

LXII

-continued o R LXV cH==cH-R nil-cook" cH-cH-R,

LXVI

CH,-ZCOOR LXVII ([TH- HR 1 OH H ICH =ZCOOR LXVIII OSOQRHI In other words, final 3-oxa and 4-oxa PGE type compounds of formula LXII (Chart E) encompass compounds of formulas XVIII to XXIII. Final 3-oxa and 4-oxa PGA type compounds of formula LXIII (Chart E) encompass compounds of formulas XXXVIII to XLIII. On the other hand. final 3-oxa and 4-oxa PGE type compounds of formula LXIX (Chart F) encompass only compounds of formulas XVIII, XIX, XXII, and XXIII, and final 3-oxa and 4-oxa PGA type compounds of formula LXX (Chart F) encompass only compounds of formulas XXXVIII, XXXIX, LXII, and XLIII.

As will subsequently appear, an acetylenic intermediate of formula LIX, formula LX, or formula LXVII is transformed by reduction to the corresponding cis or trans ethylenic intermediates of formulas LIX or LX, and an acetylenic intermediate of formulas LIX, LX, or LXVII, or a cis or trans ethylenic intermediate of formulas LIX or LX is transformed by reduction to the corresponding saturated intermediate of formulas LIX, LX, or LXVII.

The initial bicyclo-ketone reactant of formula LXV in Chart F is also used as an initial reactant to produce the initial bicyclo-ketone cyclic ketal reactant of formula LVIII in Chart E. The reactions of Chart G will product cyclic ketal LVIII. Therein THP is tetrahydropyranyl, and d), is phenyl.

The bicyclo-ketone reactant of formula LXV exists in four isomeric forms, exo and endo with respect to the attachment of the -CH=CH--R molety, and cis and trans with respect to the double bond in that moiety. Each of those isomers separately or various mixtures thereof are used as reactants according to this invention to produce substantially CHART G OTH P LXXII LXXIII LVIII 12 the same final 3-oxa or 4-oxa PGE or PGA type product mixture.

The process for preparing either the exo or endo configuration of the formula-LXV bicyclo-ketone is known to the art. See Belgian Pat. No. 702,477; reprinted in Farrndoc Complete Specifications, Book 714, No. 30,905, page 313, Mar. 12, 1968. See West Germany Offenlegungsschrift No. 1,937,912; reprinted in Farmdoc Complete Specifications, Book No. 14, No. 6869 R, Week R Mar. 18, 1970.

In said Belgian Pat. No. 702,477, a reaction sequence capable of forming exo ketone LXV is as follows: The hydroxy of 3-cyclopentenol is protected, for example, with a tetrahydropyranyl group. Then a diazoacetic acid ester is added to the double bond ot give an exoendo mixture of a bicyclo[3.l.0]hexane substituted at 3 with the protected hydroxy and at 6 with a esterified carboxyl. The exo-endo mixture is treated with a base to isomerize the endo isomer in the mixture to more of the exo isomer. Next, the carboxylate ester group at 6 is transformed to analdehyde group, CI-IO. Then, said aldehyde group is transformed by the Wittig reaction, in this case to a moiety of the formula CH=)t Cl-IR which is in exo configuration relative to the bicycle ring structure. Next, the protective group is re- 32 moved to regenerate the 3-hydroxy which his then oxidized, for example, by the Jones reagent, i.e., chromic acid (see J. Chem. Soc. 39 (1946)), to give said exo ketone LXV.

Separation of the cis-exo and trans-exo isomers of LXV is described in said Belgian Pat. No. 702, 477. However, as mentioned above, that separation is usually not necessary since the cis-trans mixture is useful as a reactant in the next process step.

The process described in said Belgian Pat. No, 702,477 producing the exo form of bicyclo-ketone LXV uses, as an intermediate, the exo form of a bicyclo [3.1.0]hexane substituted at 3 with a protected hydroxy, e.g., tetrahydropyranyloxy, and at 6 with an esterified carboxyl. When the corresponding endo compound is substituted for that exo intermediate, the process in said Offenlegungsschrift NO. 1,937,912 leads to the endo form of bicycle-ketone LXV. That endo compound to be used has the formula:

COUCH: LXXIV Compound LXXIV is prepared by reacting endo-bicyclo[3.1.0]-hexane-3-ol-6-carboxylic acid methyl ester which is then reacted with dihydropyan in the presence of a catalytic amount of POCl to give the desired compound. This is then used asdescribed in said Offenlegungsschrift No. 1.93 7,912 to product the endo form of bicycle-ketone LXV.

As for exo LXV, the above process produces a mixture of endo-cis and endo-trans compounds. These are separated as described for the separation of exo-cis and exo-trans LXV, but this separation is usually not necessary since, as mentioned above, the cis-trans mixture is useful as a reactant in the next process step.

In the process of said Belgian patent and said Offenlegungsschrift, certain organic halides, e.g., chlorides and bromides, are necessary to prepare the Wittig reagents used to generate the generic moiety, -CI-I=)t CH-R of bicycle-ketone LXV. These organic chlorides and bromides R CI-I -Cl and R CH -Br, are known in the art or can be prepared by methods known in the art.

To illustrate the availability of these organic chlorides consider first the above-described 3-oxa and 4-oxa PGE-type compounds of formulas XVIII to XXVII wherein G is alkyl of one to 10 carbon atoms, inclusive, substituted with zero, one, 2, or 3 fluoro.

For those products wherein R is alkyl of one to 10 carbon atoms, substituted with zero to 3 fluoro atoms, there are available the monohalo hydrocarbons, e.g., bromo(or chloro-)methane, -ethane, -propane, -pentane, -octane, and -decane; and the monohalofluorohydrocarbons, e.g., Cl-l FCl, CH FCH Br, CI-IF Cl-I Cl, CF Cl-l Br, F(CI-l -,Br, CH CF CH CI, CF (CH Br,

CH (CH CF (CH CH CL as described in Aliphatic Fluorine Compounds, A.M. Lovelace et al.,

.33 Am. Chem. Soc. Monograph Series 1958, Reinhold PUbl. Corp. Those halides not available are prepared by methods known in the art by reacting the corresponding primery alcohol R -CH OH with PCl PBr or any of the other halogenating agents useful for this purpose. Available alcohols include CH CH(CF )Cl-l Ol-l, (CH CHCl-l Cl-l OH,

(CH CCH OH, CF CH(CH )CH CH OH, for example. For those halides of the formula R -Cl-l -Ha1 wherein Hal is chloro or bromo R is R (CH being one, 2, 3, or 4, and R being isobutyl, tert-butyl, 3,3- difiuorobutyl, 4,4-difluorobutyl, or 4,4,4-trifluorobutyl, the intermediate alcohols are prepared as follows.

In the case of R being isobutyl or tert-butyl, known alcohols are converted to bromides, thence to nitriles with sodium cyanide, thence to the corresponding carboxylic acids by hydrolysis, and thence to the corresponding primary alcohols by reduction, e.g. with lithium aluminum hydride, thus extending the carbon chain one carbon atom at a time until all primary alcohols are prepared.

In the case of R being 3,3-difluorobutyl, the necessary alcohols are prepared from keto carboxylic acids of the formula, CH CO(CH ),-COOH, wherein r is 2, 3, 4, 5, or 6. All of those acids are known. The methyl esters are prepared and reacted with sulfur tetrafiuoride to produce the corresponding CH -CF- (CH ),COOCl-l compounds, which are then reduced with lithium aluminum hydride to CH CF- (CH Cl-l Ol-l. These alcohols are then transformed to the bromide or chloride by reaction with PBr or PCl In the case of R being 4,4-difluorobutyl, the initial reactants are the known dicarboxylic acids, HOO- C-(CH );-COOH, wherein f is 3, 4, 5, 6, or 7. These dicarboxylic acids are esterified to CH OOC-(CH ),COOCH and then half-saponified, for example with barium hydroxide, to give HOOC(CH ),COOCH The free carboxyl group is transformed first to the acid chloride with thionyl chloride and then to an aldehyde by the Rosenmund reduction. Reaction of the aldehyde with sulfur tetrafluoride then gives CHF -(CH ),-COOCH which by successive treatment with lithium aluminum hydride and PB,;, or PCl gives the necessary bromides or chlorides, CHF (CH ),-CH Br or CHF -(CH ),CH CL In the case of R being 4,4,4-trifluorobutyl, aldehydes of the formula CH OOC(Cl-l ),CHO are prepared as described above. Reduction of the aldehyde with sodium borohydride gives the alcohol CH OOC(CH -CH OH. Reaction with a hydrogen halide, for example hydrogen bromide, gives the corresponding halocarboxylic acid which by reaction with sulfur tetraflu-oride gives the necessary CF -(CH ),CH Br or CF -(CH ),CH -Cl.

For the above reactions of SE see US. Pat. No. 3,211,723 and J. Org. Chem. 27, 3164 (1962).

As mentioned above, formula XVlll-to-LVll compounds with an alpha-fluoro substitutent in a straight chain 3 to 7-carbon R i.e., R being -CHF(CH Cl-l wherein g is one, 2, 3, 4, or 5, represent preferred embodiments among the novel 3-oxa and 4-oxa compounds of this invention. Among those, for example, is 3-oxa-16-fluoro-PGE The formula-LXV bicycloketones necessary to produce those monofluoro compounds are advantageously prepared by reacting either of the above-mentioned bicyclo-aldehydes, exo or endo, with a Wittig reagent prepared from CH 34 (cH2),-Co-cH -Br and triphenylphosphine. The aldehyde group is thereby transformed to The resulting unsaturated ketone is reduced to the corresponding compound. Then -OH in that group is replaced with fluoro by known methods, for example, directly by reaction with 2-chloro-1,1,l-trifluorotriethylamine or indirectly, for example, by transforming the hydroxy to tosyloxy or mesyloxy, and reacting the resulting compound with anhydrous potassium fluoride in diethylene glycol.

The transformation of bicyclo-ketone-olefin LXV to glycol LXXlll is carried out by reacting olefin LXV with a hydroxylation reagent. Hydroxylation reagents and procedures for this purpose are known in the art. See, for example, Gunstone, Advances in Organic Chemistry, Vol. 1, pp. 103-147, lnterscience Publishers, New York, NY. (1960). Especially useful hydroxylation reagents for this purpose are osmium tetroxide and performic acid (formic acid plus hydrogen peroxide). Variousisomeric glycols are obtained depending on such factors as whether olefin LXV is cis or trans and endo or exo, and whether a cis or a trans hydroxylation reagent is used. These various glycol mixtures can be separated into individual isomers by silica gel chromatography. However, this separation is usually not necessary, since all isomers of a particular glycol are equally useful as intermediates according to this invention and the processes outlined in Chart E to produce final products of formulas LXll and LXlll, and then, according to Chart A, B, C, and D to product the other final products of this invention.

The transformation of glycol LXXIll to the cyclic ketal of formula LVlll (Chart E) is carried out by reacting said glycol with a dialkyl ketone of the formula wherein R and R are alkyl of one to 4 carbon atoms, inclusive, in the presence of an acid catalyst, for example potassium bisulfate or aqueous perchloric acid. A large excess of the ketone and the absence of water is desirable for this reaction. Examples of suitable dialkyl ketones are acetone, methyl ethyl ketone, diethyl ketone, methyl propyl ketone, and the like. Acetone is preferred as a reactant in this process.

Referring again to Chart E, cyclic ketal LVlll is transformed to cyclic ketal LIX by alkylating with an alkylation agent of the formula Hal-CH -V-COOR wherein R and V are as defined above, and Hal is chlorine, bromine, or iodine. Similarly, referring to Chart F, olefin LXV is transformed to olefin LXVl by alkylating with an alkylation agent of the formula Hal- CH -Z-COOR wherein R Z, and Hal are as defined above.

Any of the alkylation procedures known in the art to be useful for alkylating cyclic ketones with alkyl halides and haloalkanoic esters are used for the transformations of LVIIl to LIX and LXV to LXVI. See. for example, the abovementioned Belgian Pat. No. 702,477 for procedures useful here and used there to carry out similar alkylations, e.g., employing the bicyclo enamines.

For these alkylations, it is preferred that Hal be bromo ro iodo. Any of the usual alkylation bases, e.g., alkali metal alkoxides, alkali metal amides, and alkali metal hydrides, are useful for this alkylation. Alkali metal alkoxides are preferred, especially tert-alkoxides. Sodiudm and potassium are preferred alkali metals. Especially preferred is potassium tert-butoxide. Preferred diluents for this alkylation are tetrahydrofuran and 1,2- dimethoxyethane. Otherwise, procedures for producing and isolating the desired formula LIX and LXVI compounds are within the skill of the art.

These alkylation procedures produce mixtures of alpha and beta alkylation products, i.e. a mixture of the formula-LIX products wherein the CH- -VCOOR moiety is attached in alpha configuration, with corresponding compounds having that moiety attached in beta configuration, or a mixture of the formula-LXVI products with corresponding compounds having the CH -ZCOOR moiety in the beta configuration. When about one equivalent of base per equivalent of formula LXV or LVIII ketone is used, the alpha configuration usually predominates. Use of an excess of base and longer reaction times usually result in production of larger amounts of beta products. These alphabeta isomer mixtures are separated at this stage or at any subsequent stage in the multi-step processes shown in Charts E and F. Silica gel chromatography is preferred for this separation.

The necessary alkylating agents for the abovedescribed alkylations, i.e., compounds of the formulas HalCI-l VCOOR and HalCH ZCOOR are prepared by methods known in the art.

There are eight groups of compounds encompassed by these two genera of alkylating agents. Alkylating agents of the formula HalCH -ZCOOR include compounds of the following formulas:

V-COOR include the above-listed compounds of formulas LXXV, LXXVI, LXXVII, and LXXVIII, and also compounds of the following formulas:

These alkylating agents of formulas LXXV to LXXXIl are accessible to those of ordinary skill in the art. For example, the 3-oxa alkylating agents of formulas LXXV, LXXVII, LXXIX, and LXXX are advantageously prepared by reacting an alpha-hydroxy ester or acid of the formula HOCR R COOR wherein R R and R are as defined above, with a compound of the formula, JCH CnH ,,G, J CH C- I CC,,H G, and JCH -CH=CH-C H ,,G, respectively, wherein C,,H and C l l are as defined above, J is chloro, bromo, iodo, or a group transformable to one of those, for example, tetrahydropyranyloxy or mesyloxy, and G is chloro, bromo, iodo, mesyloxy, tosyloxy, or the like, in the presence of a strong base, for example, sodium hydride when R, is a carbon-containing group, and lithium diisopropyl amide when R, is hydrogen. Alternatively, an alphabromo ester or acid of the formula BrCR R COOR wherein R R and R are as defined above, is reacted in the presence of a similar strong base with a compound of the formula JCH C H ,,OH, J --CH C CC,,H ,,OH, or J CH- CH=CH-C,,H ,,OH. When both R and R in the ester are alkyl, it is preferred to use the hydroxy acid or ester route. When there are two alkyl groups in C l-l or C l-1 on the carbon to which OH or G is attached, it is preferred to use the bromo acid or ester route. When a formula LXXV, LXXVII, LXXIX, or LXXX alkylating agent is desired wherein both R and R are alkyl and C H or C H2 has two alkyl groups attached to the carbon to which -O is attached, it is preferred that G be mesyloxy or tosyloxy, or that the Br of the bromo acid or ester be replaced with mesyloxy or tosyloxy, whereupon bases and reaction conditions known in the art may be used, for example, potassium tert-butoxide in dimethyl sulfoxide. Alternatively, this group of tetraalkyl compounds is advantageously prepared by using the hydroxy acid or ester route with a compound wherein G is chloro, or by using the bromo acid or ester route wherein the bromo is replaced with chloro, using freshly precipitated wet magnesium hydroxide in an inert solvent suspension as the base. Alternatively this group of tetraalkyl compounds is advantageously prepared by the hydroxy acid or ester route wherein G is iodo, and silver oxide is used as the base. Any of these alternative routes is, of course, useful to make the other compounds within the scope of formulas LXXV, LXXVII, LXXIX, and LXXX.

37 An alternative procedure generally applicable to the production of the alkylating agents of formulas LXXV, LXXVlI, LXXIX, and LXXX comprises reacting a compound of the formula JCH C,,H ,,OH, JCH C I! CC H OH, or JCH CH=)\ CHC,,H ,,OH with an ethylerie oxide of the formula wherein R and R are as defined above, in the presence of an acid catalyst, e.g., hydrochloric acid, sulfuric acid, or boron trifluoride. The alcohol which is usually the major protuct, i.e., JCH C,,H ,,OCR R CH OH, J-CH C I CC,,H ,,OCR R CH OH, or cis or trans J-CH CH=CHC,,H- ,,OCR R CH OH, is isolated, oxidized to the corresponding carboxylic acid with Jones reagent, and the acid esterified (R The 4-oxa alkylating agents of formulas LXXVI, LXXVIII, LXXXI, and LXXXII are advantageously prepared as described above for the 3-oxa compounds, combining compounds of the formula J CH CmH- mG, J CH -CmH mOl-l, JCH C- I CCqH G, JCH C CCql-l qOl-l, JCH CH=Cl-l-Cql-l qG, and JCH CH=A CHCqH OH, with B-hydroxy acids or esters and B-halo acids or esters of the formulas HOCR R -CR R COOR, and Br-CR R CR lQ-COOR, or trimethylene oxides of the formula R R C-CR R -CH -O. All the procedures, preferences, and alternatives described above for the preparation of the 3-oxa alkylating agents are applicable to the preparation of these 4-oxa alkylating agents.

The alkylating agents of formulas LXXV to LXXXII are esters. When an alpha or beta hydroxy acid or bromo acid is used as a reactant as described above, the resulting product is a carboxylic acid. This acid is esterified to the corresponding formulas LXXV-to-LXXXII alkylating agent by known procedures. As will be described hereinafter, the ester moiety R is chosen according to the desired type of final 3-oxa or 4-oxa prostaglandin-like product.

The alpha-hydroxy, alpha-halo, beta-hydroxy, and beta-halo acids and esters and the ethylene and trimethylene oxides used as described above to produce the formula LXXV to LXXXII alkylating agents are all known in the art or are readily accessible through known methods to those of ordinary skill in the art.

The other reactants of the formulas J -CH C,,H- ,,OH, JCH --C,,,H ,,,OH, JCH -C- I CC,,H ,,-OH, JCH CH=CH-C,,H ,,OH, J--CH C C-C H Ol-l, JCH CH= Cl-lC l-l -OH, and the corresponding reactants with halogen, mesyloxy, or tosyloxy in place of OH also are known in the art or are readily accessible through known methods to those of ordinary skill in the art.

For example, consider the compounds wherein THP represents 2-tetrahydropyranyl, and each free valence is attached to hydrogen or to alkyl, with 38 a total of Zero to 9 attached alkyl carbon atoms. Said compounds are within the scope of J-CH -CnH- nOH as above defined, and are advantageously prepared by hydroxylating by known methods, olefins of the formula to give the glycols HO-CH2- COH.

which are transformed by known methods to the above tetrahydropyranyl ethers. These ethers are also transformed by known methods to compounds within the scope of JCl-l C,,H ,,G as above defined.

Consider the compounds wherein THP is as above defined, and the free valences are attached to hydrogen or to alkyl, with a total of zero to 8 attached alkyl carbon atoms. Said compounds are within the scope of J--CH C,,H ,.OH as above defined, and are advantageously prepared by known methods from beta-hydroxyesters of the formula wherein R is methyl or ethyl and the free valences are attached to hydrogen or to alkyl. Said esters are available through methods known in the art, e.g., the Reformatsky reaction. Said compounds are also transformed by known methods to compounds within the scope of JCH C,,H ,.G as above defined.

Consider the compounds 

1. AN OPTICALLY ACTIVE COMPOUND OF THE FORMULA:
 2. A racemic compound according to claim
 1. 3. An optically active compound according to claim
 1. 4. A compound according to claim 3 wherein CnH2n is straight chain alkylene of one to 5 carbon atoms, inclusive.
 5. A compound according to claim 4 wherein CnH2n is trimethylene.
 6. A compound according to claim 5 wherein R5 and R6 are hydrogen or methyl, being the same or different.
 7. A compound according to claim 6 wherein R5 and R6 are hydrogen.
 8. A compound according to claim 7 wherein R2 is pentyl.
 9. A compound according to claim 8 wherein Q is
 10. A compound according to claim 8 wherein Q is
 11. A compound according to claim 10 wherein R1 is hydrogen or alkyl of one to 4 carbon atoms, inclusive, including the pharmacologically acceptable salts thereof when R1 is hydrogen.
 12. A compound according to claim 11 wherein R1 is hydrogen or alkyl of one to 4 carbon atoms, inclusive.
 13. A compound according to claim 12 wherein R1 is hydrogen, methyl, or ethyl.
 14. 4-Oxa-PGE1, a compound according to claim
 13. 15. 4-Oxa-PGE1, methyl ester, a compound according to claim
 13. 16. 15-Methyl-4-oxa-PGE1, a compound according to claim
 13. 17. 15-Methyl-4-oxa-PGE1, methyl ester, a compound according to claim
 13. 18. An optically active compound of the formula:
 19. A racemic compound according to claim
 18. 20. An optically active compound according to claim
 18. 21. A compound according to claim 20 wherein CnH2n is straight chain alkylene of one to 5 carbon atoms, inclusive.
 22. A compound according to claim 21 wherein CnH2n is trimethylene.
 23. A compound according to claim 22 wherein R5 and R6 are hydrogen or methyl, being the same or different.
 24. A compound according to claim 23 wherein R5 and R6 are hydrogen.
 25. A compound according to claim 24 wherein R2 is pentyl.
 26. A compound according to claim 25 wherein Q is
 27. A compound according to claim 25 wherein Q is
 28. A compound according to claim 27 wherein R1 is hydrogen or alkyl of one to 4 carbon atoms, inclusive, including the pharmalogically acceptable salts thereof when R1 is hydrogen.
 29. A compound according to claim 28 wherein R1 is hydrogen or alkyl of one to 4 carbon atoms, inclusive.
 30. A compound according to claim 29 wherein R1 is hydrogen methyl, or ethyl.
 31. A compound according to claim 30 wherein the C-5 to C-6 double bond in the carboxyl-terminated side chain is in the cis configuration.
 32. 4-Oxa-PGE2, a compound according to claim
 31. 33. 4-Oxa-PGE2, methyl ester a compound according to claim
 31. 34. 15-Methyl-4-oxa-PGE2, a compound according to claim
 31. 35. 15-Methyl-4-oxa-PGE2, methyl ester, a compound according to claim
 31. 36. An optically active compound of the formula:
 37. A racemic compound according to claim
 36. 38. An optically active compound according to claim
 36. 39. A compound according to claim 38 wherein CnH2n is straight chain alkylene of one to 5 carbon atoms, inclusIve.
 40. A compound according to claim 39 wherein CnH2n is trimethylene.
 41. A compound according to claim 40 wherein R5 and R6 are hydrogen or methyl, being the same or different.
 42. A compound according to claim 41 wherein R5 and R6 are hydrogen.
 43. A compound according to claim 42 wherein R2 is pentyl.
 44. A compound according to claim 43 wherein Q is
 45. A compound according to claim 43 wherein Q is
 46. A compound according to claim 45 wherein R1 is hydrogen or alkyl of one to 4 carbon atoms, inclusive, including the pharmacologically acceptable salts thereof when R1 is hydrogen.
 47. A compound according to claim 46 wherein R1 is hydrogen or alkyl of one to 4 carbon atoms, inclusive.
 48. A compound according to claim 47 wherein R1 is hydrogen, methyl, or ethyl.
 49. 4-Oxa-5,6-didehydro-PGE1, a compound according to claim
 48. 50. 4-Oxa-5,6-didehydro-PGE1, methyl ester, a compound according to claim
 48. 51. 15-Methyl-4-oxa-5,6-didehydro-PGE1, a compound according to claim
 48. 52. 15-Methyl-4-oxa-5,6-didehydro-PGE1, methyl ester, a compound according to claim
 48. 53. An optically active compound of the formula:
 54. A racemic compound according to claim
 53. 55. An optically active compound according to claim
 53. 56. A compound according to claim 55 wherein CnH2n is straight chain alkylene of one to 5 carbon atoms, inclusive.
 57. A compound according to claim 56 wherein CnH2n is trimethylene.
 58. A compound according to claim 57 wherein R5 and R6 are hydrogen or methyl, being the same or different.
 59. A compound according to claim 58 wherein R5 and R6 are hydrogen.
 60. A compound according to claim 59 wherein R2 is pentyl.
 61. A compund according to claim 60 wherein Q is
 62. A compound according to claim 60 wherein Q is
 63. A compound according to claim 62 wherein R1 is hydrogen or alkyl of one to 4 carbon atoms, inclusive, including the pharmacologically acceptable salts thereof when R1 is hydrogen.
 64. A compound according to claim 63 wherein R1 is hydrogen or alkyl of one to 4 carbon atoms, inclusive.
 65. A compound according to claim 64 wherein R1 is hydrogen, methyl, or ethyl.
 66. 4-Oxa-13,14-dihydro-PGE1, a compound according to claim
 65. 67. 4-Oxa-13,14-dihydro-PGE1, methyl ester, a compound according to claim
 65. 68. 15-Methyl-4-oxa-13,14-dihydro-PGE1, a compound according to claim
 65. 69. 15-Methyl-4-oxa-13,14-dihydro-PGE1, methyl ester, a compound according to claim
 65. 70. An optically active compound of the formula: 